Department of Physiology, The University of Louisville School of Medicine, Louisville, KY, USA.
Department of Physiology, The University of Louisville School of Medicine, Louisville, KY, USA.
Pharmacol Res. 2019 Sep;147:104391. doi: 10.1016/j.phrs.2019.104391. Epub 2019 Aug 8.
This review article discusses recent advances in the mechanism of dipeptidyl peptidase-4 (DPP-4) actions in renal diseases, especially diabetic kidney fibrosis, and summarizes anti-fibrotic functions of various DPP-4 inhibitors in diabetic nephropathy (DN).
DN is a common complication of diabetes and is a leading cause of the end-stage renal disease (ESRD). DPP-4 is a member of serine proteases, and more than 30 substrates have been identified that act via several biochemical messengers in a variety of tissues including kidney. Intriguingly, DPP-4 actions on the diabetic kidney is a complex mechanism, and a variety of pathways are involved including increasing GLP-1/SDF-1, disrupting AGE-RAGE pathways, and integrin-β- and TGF-β-Smad-mediated signalling pathways that finally lead to endothelial to mesenchymal transition. Interestingly, an array of DPP-4 inhibitors is well recognized as oral drugs to treat type 2 diabetic (T2D) patients, which promote better glycemic control. Furthermore, recent experimental and preclinical data reveal that DPP-4 inhibitors may also exhibit protective effects in renal disease progression including anti-fibrotic effects in the diabetic kidney by attenuating above signalling cascade(s), either singly or as a combinatorial effect. In this review, we discussed the anti-fibrotic effects of DPP-4 inhibitors based on recent reports along with the possible mechanism of actions and future perspectives to underscore the beneficial effects of DPP-4 inhibitors in DN.
With recent experimental, preclinical, and clinical evidence, we summarized DPP-4 activities and its mechanism of actions in diabetic kidney diseases. A knowledge gap of DPP-4 inhibition in controlling renal fibrosis in DN has also been postulated in this review for future research perspectives.
本文讨论了二肽基肽酶-4（DPP-4）在肾脏疾病中的作用机制的最新进展，特别是糖尿病肾病纤维化，并总结了各种 DPP-4 抑制剂在糖尿病肾病中的抗纤维化作用。
糖尿病肾病是糖尿病的常见并发症，也是终末期肾病（ESRD）的主要原因。DPP-4 是丝氨酸蛋白酶家族的一员，在包括肾脏在内的多种组织中，已经鉴定出 30 多种通过多种生化信使发挥作用的底物。有趣的是，DPP-4 在糖尿病肾脏中的作用机制很复杂，涉及多种途径，包括增加 GLP-1/SDF-1、破坏 AGE-RAGE 途径以及整合素-β和 TGF-β-Smad 介导的信号通路，最终导致内皮细胞向间充质转化。有趣的是，一系列 DPP-4 抑制剂已被广泛认可为治疗 2 型糖尿病（T2D）患者的口服药物，可通过改善血糖控制来发挥作用。此外，最近的实验和临床前数据表明，DPP-4 抑制剂也可能在肾脏疾病进展中表现出保护作用，包括通过减轻上述信号级联反应（单独或作为组合效应）来减轻糖尿病肾脏中的抗纤维化作用。在本综述中，我们根据最近的报道讨论了 DPP-4 抑制剂的抗纤维化作用，以及可能的作用机制和未来展望，以强调 DPP-4 抑制剂在糖尿病肾病中的有益作用。
有了最近的实验、临床前和临床证据，我们总结了 DPP-4 在糖尿病肾脏疾病中的活性及其作用机制。本文还提出了 DPP-4 抑制在控制糖尿病肾病肾纤维化方面的知识空白，以供未来研究展望。
